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From the Research Institute of Angiocardiology and the Second Department
of Internal Medicine (K.T.), Kyushu University Faculty of Medicine, Fukuoka,
Japan.
Correspondence to Kensuke Egashira, MD, PhD, Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University School of Medicine, 3–1-1, Maidashi, Higashi-ku, Fukuoka 812–82, Japan. E-mail egashira{at}cardiol.med.kyushu-u.ac.jp
Abstract—We previously reported that
the chronic inhibition of nitric oxide (NO) synthesis increases cardiac
tissue angiotensin-converting enzyme expression and causes
cardiac fibrosis in rats. However, the mechanisms are not known.
Transforming growth factor-ß (TGF-ß) is a key molecule that is
responsible for tissue fibrosis. The present study investigated the
role of TGF-ß in the pathogenesis of cardiac fibrosis. The
development of cardiac fibrosis by oral administration of the NO
synthesis inhibitor
N
© 1998 American Heart Association, Inc.
Scientific Contributions
Early Induction of Transforming Growth Factor-ß via Angiotensin II Type 1 Receptors Contributes to Cardiac Fibrosis Induced by Long-term Blockade of Nitric Oxide Synthesis in Rats
-nitro-L-arginine methyl
ester (L-NAME) to normal rats was preceded by increases in mRNA levels
of cardiac TGF-ß1 and extracellular matrix (ECM)
proteins. TGF-ß immunoreactivity was increased in the areas of
fibrosis. Treatment with a specific angiotensin II type 1
receptor antagonist, but not with hydralazine,
completely prevented the L-NAME–induced increases in the gene
expression of TGF-ß1 and ECM proteins and also prevented
cardiac fibrosis. Intraperitoneal injection of
neutralizing antibody against TGF-ß did not affect the
L-NAME–induced increase in TGF-ß1 mRNA levels but
prevented an increase in the mRNA levels of ECM protein. These results
suggest that the early induction of TGF-ß1 via the
angiotensin II type 1 receptor plays a major role in the
development of cardiac fibrosis in this model.
Key Words: endothelium-derived relaxing factor • remodeling • growth substances • collagen • angiotensin II
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